The present invention relates to novel benzopyrans having pharmacological activity, to a process for preparing them, to pharmaceutical compositions containing them, and to their use in the treatment of hypertension.
Quagliato et al (U.S. Ser. No. 146,875, filed Jan. 22, 1988) discloses classes of chromans that are described as having blood pressure lowering activity. European Patent Publication 158,923 discloses classes of chromans that are described as having blood pressure lowering activity. In addition, U.S. Pat. Nos. 4,616,021 and 4,251,537 disclose classes of chromans that are described as having blood pressure lowering activity.
The present invention discloses compounds represented by formula (I) ##STR1## werein R.sup.1 is trifluoromethylsulfonyl or trifluoromethylsulfinyl and R.sup.2 is H; or R.sup.1 is H or nitro and R.sup.2 is CF.sub.3 CONH.
The compounds of formula (I), are asymmetric and, therefore, can exist in the form of optical isomers. The present invention extends to all such isomers individually and as mixtures, such as racemic modifications.
Preferably, a compound of formula (I) is in substantially pure form.
Examples of compounds of formula (I) include the compounds prepared in the Examples hereinafter.
The present invention also provides a process for the preparation of a compound of formula (I), which comprises the reaction of a compound of formula (II) ##STR2## wherein R.sup.1 and R.sub.B.sup.2 are R.sup.1 and R.sup.2 as defined respectively, hereinbefore or a group or atom convertible thereto with a compound of formula (III) ##STR3## under reductive amination conditions.
It is particularly preferred that the reaction between the compounds of formula (II) and (III) is carried out under reducing conditions so as to facilitate the formation of the desired bonds, for example by warming in the presence of sodium cyanoborohydride.
Examples of conversions of a group or atom from R.sub.A.sup.1 into R.sup.1 and R.sub.B.sup.2 into R.sup.2 are generally known in the art of synthetic chemistry. For example, if it is desired to obtain a compound of formula (I) wherein R.sup.1 is nitro and R.sup.2 is CF.sub.3 CONH, it is possible to convert a compound of formula (I) wherein R.sup.1 is H and R.sup.2 is NH.sub.2 or a protected NH.sub.2 to the desired R.sup.1 is NO.sub.2 and R.sup.2 is CF.sub.3 CONH by nitration under standard conditions. Examples of protecting agents and their addition and removal are generally known in the art.
As mentioned previously, the compounds of formula (I) have been found to have blood-pressure lowering activity. They are therefore useful in the treatment of hypertension. Furthermore the compounds of formula (I) are active potassium channel activators which renders them useful in the treatment of cardiovascular diseases such as peripheral vascular disease, angina, congestive heart failure, and cerebral vascular disease, and in disorders involving excessive smooth muscle contraction of the gastro-intestinal tract (such as irritable bowel syndrome), respiratory system (such as asthma and reversible airways obstruction) and urinary tract (such as incontinence). Further, these compounds are useful in the treatment of baldness and hair loss.
The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention and a pharmaceutically acceptable carrier. In particular, the present invention provides an antihypertensive pharmaceutical composition which comprises an antihypertensive effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration for patients suffering from heart failure.
In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compositions may be administered from 1 to 6 times a day, more usually 1 to 4 times a day.
The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavouring agent and the like. They are formulated in conventional manner, for example in a manner similar to that used for known antihypertensive agents, diuretics and -blocking agents.
The present invention further provides a compound of the invention for use as an active therapeutic substance. Compounds of formula (I) are of particular use in the treatment of hypertension.
The present invention further provides a method of treating hypertension in mammals including man, which comprises administering to the afflicted mammal an antihypertensive effective amount of a compound or a pharmaceutical composition of the invention.
Synthetic Process A relates to the preparation of the compounds of formula (I) ##STR4## wherein R.sup.1 is SOCF.sub.3 or SO.sub.2 CF.sub.3 and R.sup.2 is H.
Synthetic Process B relates to the compound of Formula (I) ##STR5## wherein R.sup.1 is NO.sub.2 and R.sup.2 is CF.sub.3 CONH.
The following Examples further illustrate this invention.